Mechanisms of tandem duplication in the cancer genome.

Tandem duplications (TD) are among the most frequent type of structural variant (SV) in the cancer genome. They are characterized by a single breakpoint junction that defines the boundaries and the size of the duplicated segment. Cancer-associated TDs often increase oncogene copy number or disrupt tumor suppressor gene function, and thus have important roles in tumor evolution.

Two-ended recombination at a Flp-nickase-broken replication fork.

Replication fork collision with a DNA nick can generate a one-ended break, fostering genomic instability. The opposing fork's collision with the nick could form a second DNA end, enabling conservative repair by homologous recombination (HR). To study mechanisms of nickase-induced HR, we developed the Flp recombinase "step arrest" nickase in mammalian cells.

Politics, policy and action: lessons from rural GP advocacy in Ireland.

Context: Ireland has one of the most rural populations in Europe. Rurality presents challenges when accessing health services but should not be perceived as problematic and in need of a structural fix. Structural urbanism where health care is viewed as a commodity for individuals, rather than an infrastructure for populations, innately favours larger urban populations and has detrimental outcomes for rural health.

Two-ended recombination at a Flp-nickase-broken replication fork.

Collision of a replication fork with a DNA nick is thought to generate a one-ended break, fostering genomic instability. Collision of the opposing converging fork with the nick could, in principle, form a second DNA end, enabling conservative repair by homologous recombination (HR). To study mechanisms of nickase-induced HR, we developed the Flp recombinase "step arrest" nickase in mammalian cells.

Size thresholds for repair of abdominal aortic aneurysms warrant reconsideration.

Background: The historical size threshold for abdominal aortic aneurysm (AAA) repair is widely accepted to be 5.5 cm for men and 5.0 cm for women.

Enhancing early career professionals' representation and engagement at international conferences: WONCA "Rural Early Career Ambassador Integration" project.

Introduction: International conferences offer an excellent opportunity for career development and are global academic opportunities with the potential to foster educational and professional growth. However, equitable access to participation and meaningful involvement in such events remains an issue. In this article we describe the novel Rural Early Career Ambassador Integration project and its implications for the 2022 World Rural Health Conference, held at the University of Limerick, Ireland.

A review of pulmonary neutrophilia and insights into the key role of neutrophils in particle-induced pathogenesis in the lung from animal studies of lunar dusts and other poorly soluble dust particles.

The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals.

Sharing FAIR monitoring program data improves discoverability and reuse.

Data resulting from environmental monitoring programs are valuable assets for natural resource managers, decision-makers, and researchers. These data are often collected to inform specific reporting needs or decisions with a specific timeframe. While program-oriented data and related publications are effective for meeting program goals, sharing well-documented data and metadata allows users to research aspects outside initial program intentions.

Persistent changes in expression of genes involved in inflammation and fibrosis in the lungs of rats exposed to airborne lunar dust.

NASA is currently planning return missions to the Moon for further exploration and research. The Moon is covered by a layer of potentially reactive fine dust, which could pose a toxicological risk of exposure to explorers. To assess this risk, we exposed rats to lunar dust (LD) that was collected during the Apollo14 mission.

'The word that comes to mind is polymath': medical students' perceptions of rural postgraduate careers.

Introduction: Medical education is essential in strengthening the rural medical workforce globally. Immersive medical education in rural communities guided by good role models and rural-specific curricula promotes rural recruitment of recent graduates. While curricula can be rurally oriented, the mechanism of action is unclear.

The Limerick Declaration on Rural Health Care 2022.

The 19th World Rural Health Conference, hosted in rural Ireland and the University of Limerick, with over 650 participants coming from 40 countries and an additional 1600 engaging online, has carefully considered how best rural communities can be empowered to improve their own health and the health of those around them. The conference also considered the role of national health systems and all stakeholders, in keeping with the commitments made through the Sustainable Development Goals and the enjoyment of the highest attainable standard of health as one of the fundamental rights of every human being. This conference declaration, the Limerick Declaration on Rural Healthcare, is designed to inform rural communities, academics and policymakers about how to achieve the goal of delivering high quality health care in rural and remote areas most effectively, with a particular focus on the Irish healthcare system.

Exploiting CRISPR/Cas9 to engineer precise segmental deletions in mouse embryonic stem cells.

In this protocol, we use CRISPR/Cas9 to generate large deletions of the entire coding region of a gene of interest, generating a hemizygous cell line. Next, we systematically engineer precise in-frame deletions within the intact wild-type allele, facilitating study of multi-domain proteins. The optimized protocol described here allows us to rapidly screen for effective sgRNA pairs and to engineer either an in-frame deletion or a frameshift mutation in high frequencies in mouse embryonic stem cells.

The structure-specific endonuclease complex SLX4-XPF regulates Tus-Ter-induced homologous recombination.

Vertebrate replication forks arrested at interstrand DNA cross-links (ICLs) engage the Fanconi anemia pathway to incise arrested forks, 'unhooking' the ICL and forming a double strand break (DSB) that is repaired by homologous recombination (HR). The FANCP product, SLX4, in complex with the XPF (also known as FANCQ or ERCC4)-ERCC1 endonuclease, mediates ICL unhooking. Whether this mechanism operates at replication fork barriers other than ICLs is unknown.

A modified CUT&RUN-seq technique for qPCR analysis of chromatin-protein interactions.

Chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) even with optimization may give low signal-to-background ratio and spatial resolution. Here, we adapted Cleavage Under Targets and Release Using Nuclease (CUT&RUN) (originally developed by the Henikoff group) to develop CUT&RUN-qPCR. By studying the recruitment of selected proteins (but amenable to other proteins), we find that CUT&RUN-qPCR is more sensitive and gives better spatial resolution than ChIP-qPCR.

Contemporary indications for open abdominal aortic aneurysm repair in the endovascular era.

Objective: Despite the emergence of endovascular aneurysm repair (EVAR) as the most common approach to abdominal aortic aneurysm repair, open aneurysm repair (OAR) remains an important option. This study seeks to define the indications for OAR in the EVAR era and how these indicatioxns effect outcomes.

Methods: A retrospective cohort study was performed of all OAR at a single institution from 2004 to 2019.

Comparative pulmonary toxicities of lunar dusts and terrestrial dusts (TiO & SiO) in rats and an assessment of the impact of particle-generated oxidants on the dusts' toxicities.

Humans will set foot on the Moon again soon. The lunar dust (LD) is potentially reactive and could pose an inhalation hazard to lunar explorers. We elucidated LD toxicity and investigated the toxicological impact of particle surface reactivity (SR) using three LDs, quartz, and TiO.

Contemporary outcomes of precision banding for high flow hemodialysis access.

Objective: High-flow hemodialysis accesses are a well-recognized source of patient morbidity. Among available management strategies inflow constriction based on real-time physiologic flow monitoring offers a technically straightforward data-driven approach with potentially low morbidity. Despite the benefits offered by this approach, large contemporary series are lacking.

The Protexin complex counters resection on stalled forks to promote homologous recombination and crosslink repair.

Protection of stalled replication forks is critical to genomic stability. Using genetic and proteomic analyses, we discovered the Protexin complex containing the ssDNA binding protein SCAI and the DNA polymerase REV3. Protexin is required specifically for protecting forks stalled by nucleotide depletion, fork barriers, fragile sites, and DNA inter-strand crosslinks (ICLs), where it promotes homologous recombination and repair.

Recombination and restart at blocked replication forks.

Replication fork stalling occurs when the replisome encounters a barrier to normal fork progression. Replisome stalling events are common during scheduled DNA synthesis, but vary in their severity. At one extreme, a lesion may induce only temporary pausing of a DNA polymerase; at the other, it may present a near-absolute barrier to the replicative helicase and effectively block fork progression.

Lamin B1 sequesters 53BP1 to control its recruitment to DNA damage.

Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair.

'The word that comes to mind is polymath': medical students' perceptions of rural postgraduate careers.

Introduction: Physician shortages in rural and remote areas challenge accessibility and delivery of care to rural and remote communities, including within Scotland. Medical education is a reform priority to establish a sustainable medical workforce. Although there is evidence to support aspects of medical education that enhance the likelihood of practising rurally, the mechanism by which these educational initiatives work is not clearly understood.

Comparative analysis of open abdominal aortic aneurysm repair outcomes across national registries.

Objective: In a recent analysis, we discovered lower mortality after open abdominal aortic aneurysm repair (OAAA) in the Society for Vascular Surgery Vascular Quality Initiative (VQI) database when compared with previously published reports of other national registries. Understanding differentials in these registries is essential for their utility because such datasets increasingly inform clinical guidelines and health policy.

Methods: The VQI, American College of Surgeons National Surgical Quality Improvement Program (NSQIP), and National Inpatient Sample (NIS) databases were queried to identify patients who had undergone elective OAAA between 2013 and 2016.

FANCM regulates repair pathway choice at stalled replication forks.

Repair pathway "choice" at stalled mammalian replication forks is an important determinant of genome stability; however, the underlying mechanisms are poorly understood. FANCM encodes a multi-domain scaffolding and motor protein that interacts with several distinct repair protein complexes at stalled forks. Here, we use defined mutations engineered within endogenous Fancm in mouse embryonic stem cells to study how Fancm regulates stalled fork repair.

A multicenter, prospective randomized trial of negative pressure wound therapy for infrainguinal revascularization with a groin incision.

Background: Wound complications after open infrainguinal revascularization are a frequent cause of patient morbidity, resulting in increased healthcare costs. The purpose of the present study was to assess the effects of closed incision negative pressure therapy (ciNPT) on groin wound complications after infrainguinal bypass and femoral endarterectomy.

Methods: A total of 242 patients who had undergone infrainguinal bypass (n = 124) or femoral endarterectomy (n = 118) at five academic medical centers in New England from April 2015 to August 2019 were randomized to ciNPT (PREVENA; 3M KCI, St Paul, Minn; n = 118) or standard gauze (n = 124).